Key Mutation May Suppress the Immune System in Melanoma

It may be possible to combat melanoma in a whole new way thanks to a new discovery about how the immune system responds to some melanomas.

Investigators at the University of California, Irvine (UCI) report in the journal Cell Reports, that they have uncovered a specific mutation in the ATR gene that allows melanoma tumor cells to remain undetected by the immune system. The finding may lead to the development of improved immunotherapies and more effective methods to identify patients who may respond to these new therapies.

"Cancers develop not only because they acquire mutations that promote their growth, but also because they are able to prevent the immune system from recognizing and removing them," said senior study author Anand Ganesan, MD, who is an associate professor of dermatology at the UCI.

Ganesan and colleagues identified a mutation in the ATR gene, a protein that normally recognizes and repairs UV-induced DNA damage, in melanoma tumors. Cancers with this ATR mutation suppress the body's natural immune response. The team reports that loss-of-function mutations in ATR appear to be present in human melanoma tumors. In addition, ATR-mutant nevi and melanomas appear to grow larger than tumors that have functional ATR. 

These findings may turn out to be clinically significant because ATR-mutant tumors are able to enlist pro-tumorigenic macrophages and block T-cell recruitment, according to the researchers. In addition, the team reports that ATR mutations accelerate tumor growth by altering the tumor microenvironment.

The researchers identified a specific subset of human melanomas that have loss-of-function mutations in ATR. They report that ATR-mutant tumors exhibited both the accumulation of multiple mutations and the altered expression of inflammatory genes. This resulted in decreased T-cell recruitment and it appeared to increase recruitment of macrophages known to spur tumor invasion. It is hoped that these findings will lead to new ways of correcting a mechanism by which melanoma cells modulate the immune microenvironment to promote continued growth.

Ganesan said previous work by other investigators demonstrated that hypomorphic mutations in ATR are observed in Seckel syndrome, a recessive disorder that is characterized by developmental delay as well as premature aging. Using an ATR-mutant mice model, investigators in previous studies have found signs of premature aging and greying of hair. Partial loss-of-function ATR mutations have also been associated with an oropharyngeal cancer syndrome.